Waging War on Modern Chronic Diseases Primary Prevention Through Exercise Biology

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    88:774-787, 2000.J Appl PhysiolFrank W. Booth, Scott E. Gordon, Christian J. Carlson and Marc T. Hamiltonprevention through exercise biologyWaging war on modern chronic diseases: primary

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    invited review

    Wa ging w a r on modern chronic disea ses:primary prevention through exercise biology

    FRANK W. B OOTH, SC OTT E. G ORDON, 1

    CH RIS TIAN J . C ARLS ON,1 AND MARC T. H AMILTON 2

    1Department of Integrative Biology, University of Texas Medical School,H ouston, Texas 77030; and 2Departm ent of Veter in ar y Bi omedical Sciences,College of Veterinary Medicine, University of Missouri, Columbia, Missouri 65211

    Booth, Fr ank W., Scott E. Gordon, C hristian J . Carlson, andMarc T. Hamilton. Wa ging w a r on modern chronic dis ea s es : prima ry

    prevention thr ough exercise biology. J . A p p l . P h y s i o l . 88: 774787,2000. I n t his review, w e develop a blueprint for exercis e biologyres ea rch in t he new millennium. The fi rs t pa rt of our pla n providess t a t i s t ics t o s u p por t t h e co nt e n t ion t h a t t h e r e h a s b ee n a n e pi d em i cemergence of modern chronic dis ea s es in t he la t t er pa rt of t he 20t hcentur y. The hea lth care costs of these conditions w ere alm ost tw o-thirdsof a t r i l l ion dolla rs a nd a f fect ed 90 million America ns in 1990. Wees t ima t e t ha t t hes e cos t s a re now a pproa ching $1 t r i l l ion a nd s t a nd t of u rt h e r d r a m a t i c a l ly i n cr e a s e a s t h e b a b y b oom g e ne r a t i on a g e s . Wedis cus s t he rea ct ion of t he biomedica l es t a blishment t o t his epidemic,which ha s primar ily been to apply modern technologies to sta bilize overtclinical problems (e.g. , secondary and tertiary prevention). Because thisa pproa ch ha s been la rgely uns ucces s ful in revers ing t he epidemic, w ea rgue t ha t more empha s is mus t be pla ced on novel a pproa ches s uch a sprimary prevention, which requires attacking the environmental roots of

    these conditions. In this respect, a strong association exists between theincrea s e in phys ica l ina ct ivit y a nd t he emergence of modern chronicdiseases in 20th century industrialized societies. Approximately 250,000d e a t h s p e r y e a r i n t h e U n i t e d S t a t e s a r e p r e m a t u r e d u e t o p h y s i c a linactivity. Epidemiological data have established that physical inactivityincreases the incidence of at least 17 unhealthy conditions, almost all ofwhich are chronic diseases or considered risk factors for chronic diseases.Therefore, as pa rt of this r eview, we present t he concept t ha t t he huma ngenome evolved wit hin a n environment of high physical a ctivity. Accord-ingly, w e propos e t ha t exercis e biologis t s do n ot s t udy t he effect ofphysical a ctivity but in rea lity st udy t he effect of reintroducing exerciseint o a n unh ea lt hy s edent a ry popula t ion t ha t is genet ica lly progra mmedto expect physical a ctivity. On t he ba sis of healthy gene function, exerciseresearch should thus be viewed from a nont ra ditional perspective in tha tt he cont rol group s hould a ct ua lly be t a ken from a phys ica lly a ct ive

    population an d not from a sedenta ry populat ion w ith its predisposition tomodern chronic dis ea s es . We provide excit ing exa mples of exercis ebiology resear ch that is elucidating t he underlying mechanisms by w hichphysical inactivity may predispose individuals to chronic disease condi-t ions , s uch a s mecha nis ms cont ribut ing t o ins ulin res is t a nce a nd de-crea s ed s kelet a l mus cle l ipoprot ein l ipa s e a ct ivit y. Some fi ndings ha veb ee n s u r pr i si n g a n d r e m a r ka b l e i n t h a t n ov el s i gn a l i n g m e c h a n is m sh a v e b e en d i scov er e d t h a t v a r y w i t h t h e t y p e a n d l ev el of p h y s i ca lact ivity /ina ctivit y at m ultiple levels of gene expression. B ecause th is area

    J. Appl . Physiol .88: 774787, 2000.

    8750-7587/00 $5.00 C opyr igh t 2000 the American Physiological Society774 h t t p://w w w.ja p.or g

    First in a series of invited mini-reviews on Molecular andCellular Basis of ExerciseAdaptations.

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    of resea rch is underfunded des pit e i t s high impa ct , t he fi na l pa rt of ourblueprint for t he next millennium ca lls for t he Na t iona l I ns t i t ut es ofHea lt h (NI H) t o es t a blis h a ma jor init ia t ive devot ed t o t he s t udy of t hebiology of the primary prevention of modern chronic diseases. We justifythis in several w ay s, including th e following est imat e: if the percentage ofa ll U S m orbidit y a nd mort a li t y s t a t is t ics a t t r ibut ed t o t he combina t ion ofphysical inactivity a nd ina ppropriat e diet w ere applied as a percentage oft he NI H s t ot a l opera t ing budget , t he res ult ing funds w ould equa l t hebudgets of tw o full institutes at t he NIH! F urth ermore, the fi scal supportof s t udies elucida t ing t he s cient ific founda t ion(s ) t a rget ed by prima ryprevent ion s t ra t egies in ot her public hea lt h ef fort s ha s res ult ed in a nincrea s ed eff ica cy of t he overa ll prevent ion effort . We es t ima t e t ha tphys ica l ina ct ivit y impa ct s 8090% of t he 24 int egra t ed review group(I R G ) t opics propos ed by t he NI Hs P a nel on S cient ific B ounda ries forReview, which is currently directing a major restructuring of the NIHss ci en t i fi c f u n di n g s y s t em . U n f o rt u n a t e l y, t h e p r im a r y p r ev en t i on ofchronic dis ea s e a nd t he inves t iga t ion of phys ica l a ct ivit y/ina ct ivit ya nd/or exercis e a re not ment ioned in t he a lmos t 200 t ot a l s ubt opicscompris ing t he I R Gs in t he P a nel s propos a l . We believe t his t o be agla ring omiss ion by t he P a nel a nd cont end t ha t t he current reorga niza -tion of NIHs scientifi c review a nd fundin g system is a golden opportun ityt o i n v es t i n fi e l d s t h a t s t u d y t h e b i ol og i ca l m e ch a n i s m s o f p r i m a r yprevent ion of chronic disea ses (such as exercise biology). This w ould be ani n v e s t m e n t t o a v o i d U S h e a l t h c a r e s y s t e m b a n k r u p t c y a s w e l l a s t o

    reduce the extreme huma n suffering caused by chronic diseases. In short,i t w o ul d b e a n i nv es t m en t i n t h e f ut u r e of h ea l t h ca r e i n t h e n ew millennium.

    sedentar y; environmenta l; gene; molecular biology; cell signaling; epide-miology; hea lth

    OUR SOCIETY IS ATWAR . Although it ma y not be commonlypublicized in t his ma nner, make n o mista ke, our soci-ety, and even the worlds population in general, is trulya t w a r a gainst a common enemy. Tha t enemy is modernchronic disea se.

    THE ENEMY: MODERN CHR ONIC DISEASE

    Chronic disea se is defin ed a s a disease tha t is slowin i ts p ro g re ss an d lo n g in i ts co n tin u an ce (11). A nindividua l crosses a th reshold called a clinica l horizonto m an ife st (an d b e d iag n o se d with ) a m u lti facto rialchronic disease generally years after the original causesof th e disease ha ve ta ken effect. Tha t is, t he physiologi-cal m e ch an ism s u n d e rlyin g th e se d ise ase s h ave u su -a l l y b ee n a c t i ve l on g b ef or e a p a r t i cu la r v ict i m i soutwa rdly affected. Ma jor examples of chronic diseaseare coronary heart disease (including atherosclerosis,hea rt fa ilure, hypert ension, an d st roke), obesity, Type 2diabetes, some cancers, osteoporosis, and sarcopenia(frailty in old age as a result of weak muscles). It would

    be difficult to find anyone in our society who is exemptfrom th e d e vast at in g e f fe cts of on e o r m ore ch ron icdiseases. I f a n individual does not suffer directly fromchronic disea se, they m ost likely suffer indirectly a s aresult of the stress of ca re giving to others, t he deat h offam ily m e m b ers or f r ien d s, an d /or in cre ase d h e al thcare costs.

    ARE WE WINNING THE WAR AGAINST MODERN

    CHRONIC DISEASE?

    The answer is a resounding No! There has been adra ma tic increase in the incidence of chronic disea ses

    in the latter part of the 20th century. Chronic diseasecon d it ion s cau se g re at h u m an su fferin g , a f fe ctin g 90million Americans and costing nearly two-thirds of atrillion dollars in health care expenses and lost produc-tivi ty in ou r society in 1990 (24). F u rth e rm ore , wep rovid e an e st im at e late r in th is re vie w t h at in d icat e stha t t his fi gure ma y now be approaching $1 trillion (seeTab le 2). M ore over, w e e st im at e t h at th e cost to ou rsociety resulting solely from the triad of coronary heartd ise ase , d iab e te s, an d o b e si ty alo n e is n e arly h al f atrillion dollars! True, we ha ve won some bat tles in t hep ast few d e cad e s; h o we ver, su ch fi g u res in d icat e th a tw e a r e s t i ll l os i ng t h e w a r a g a i n s t m od er n ch r on i cd i s e a s e . I t m a y c o m e a s a s h o c k t o m a n y t h a t t h ead va n ces m ad e ag a in st m od e rn ch ron ic d isease s overthe past 30 year s ha ve come to a ha lt. For exa mple, thecon te xt of a f ron t-p ag e a rt icle in th e S e p tem b er 27,1999, USA Today im plie d su rp rise wh e n qu o tin g th ech airm an o f a re ce n t co n fe re n ce o n h e art d ise ase ass a y i n g t h a t t h e d e c l i n e i n h e a r t d i s e a s e a n d s t r o k e

    deaths appears to be petering out and possibly goingb ack u p . P re viou s sta t is t ics sh owin g th e d e cre asin gpercentage of some coronary heart diseases may havema sked the urgency of our current a nd eminent futurehealth care difficulties. These and other numbers re-quir e closer ins pection.

    Sta ti stics: Casual ti es and Pr ojected L osses

    Coronary hear t di sease. Co ro n ary h e art d ise ase ac-co u n te d fo r th e vast m ajo ri ty o f d e ath s in th e Un ite dSt a tes in t he 20th cent ury (3). Since 1900, ca rdiova scu-l a r d is ea s e h a s b een t h e n u m b er on e k i ll er i n t h e

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    US every year but one (1918). Cardiovascular diseasewa s th e p rim a ry cau se of 960,000 deat hs (41%of a lld e ath s) in 1996 an d was th e p rim ary o r co n trib u tin gcause of 1.4 million deaths (60%of all deaths). Cardio-vascu lar d isease claim s m o re lives e ach ye ar th a n t h enext s even prevalent causes of dea th combined (3). TheAmerican Heart Association stated that the number ofp e o p le d yin g fro m d ise ase s o f th e h e art h as r ise n b y37% (200,000 a dditional yearly deat hs) from 1950 to1996 (3). Although a nnua l deat h r at es from cardiovas-cular disea se ha ve just recently begun t o decline (21.3%from 1986 to 1996), th e ab so lu te n u m b er of car d io-vascu lar d eat h s d e cl in e d on ly 2% in th e sam e 10-yrperi od (3).

    Type 2 di abetes. Typ e 2 d iab e tes h as b ecom e soco m m o n in o u r so cie ty th at i t h as b e e n said to h avereached epidemic proportions. A sixfold increa se inprevalence of Type 2 diabetes occurred between 1958a nd 1993 (2). Hist orically, Type 2 diabetes ha s beenconsidered a disease of adults and older individuals andnot a pediatric condition (32). However, Pinhas-Hamiel

    et a l. (46) report ed a 10-fold increa se in Type 2 dia betesb e twe e n 1982 an d 1994 in ad o le sce n ts . I n ad d it io n ,a m o n g p a t i en t s 10 19 y r of a g e , Ty p e 2 d ia b e t esaccou n te d for 33% of al l n e wly d iag n osed case s ofdiabetes in 1994. Thus the overall increa se in Type 2d iab e te s is n o t so le ly a re su lt o f th e fact th at th e USpopulation is now living longer past middle age. Thismea ns t ha t our children w ill experience Type 2-rela tedcon d it ion s su ch as re t in op ath ie s, m yo card ia l in far c-t io n s, an d stro k e s m u ch e arl ie r in l i fe . T h e n e e d toadminister medical treatment to this subpopulation atsuch an early part in their lives could place a significante co n o m ic strain o n o u r fam il ie s an d so cie ty. B u t th eg re ate st tra g e dy is th at t h e ai lm e n ts th at h ave u su ally

    been thought only to affect individuals of middle age orolder will now affect our children at a much earlier age,dra stically decrea sing their qua lity of life over a muchlonger period t ha n previous genera tions. According tot h e Am e r ica n D i a b e t es As s oc ia t i on , d i a b et e s k il ls193,000 Americans each year (2). This number is sureto rise.

    Obesity. T h e cu rre n t tre n d in o b e si ty s tat is t ics h asa lso become epidemic. Obesity w as estima ted t o annu-al ly accou n t for 280,000 325,000 d e ath s in th e USusing 1991 statistics (1), and this number is growingqu ick ly. I n th e 1988 1994 t im e p e rio d , an alarm in g63% o f ad u lt m e n an d 55% o f ad u lt wo m en in t h e USw ere cla ssifi ed as overweight or obese [body mas s index

    (B MI) of 25 kg /m 2] (40)! These numbers have beencontinua lly increasing over t he past 40 yr. Betw een th e19601962 period a nd th e 19881994 period, t he pr o-port ion of US a dults w ith class I obesity (B MI from 30t o 34.9 kg /m 2) rose 66%(or a ra te of increa se of 2.2%p e r ye ar) (16). Eve n wo rse , th is rate o f in cre ase ino b e si ty p re vale n ce ap p e ars to b e acce le rat in g , g ive nt h a t t h e p r o p o r t i o n o f U S a d u l t s w i t h a B M I o f 30kg/m 2 rose 49%betw een 1991 and 1998 or 7%per y ear(38)! Like adults, the number of overweight childrenan d ad o lesce n ts in t h e US also in cre ase d b etw e en t h e19601962 period a nd th e 19881994 period, w ith th is

    rate of increase also accelerating in the final 1012 yrof this int erva l (16). Approxima tely 11%of U S childrena n d a d o le sce nt s w e r e r ep or t e dl y ov er w e ig h t i n t h e19881994 period (55). Moreover, the 70%increase inproportion of obese persons in th e 18- to 29-yr-old a gegroup betw een 1991 and 1998 (38) indica tes t ha t th osesobering statistics in children are now translating intosimilar t rends wit hin the young adult populat ion of theU S. The obesity epidemic is t herefore like the Type 2d ia b e t es e pi d em i c in t h a t i t s a d v a n c e i s n o t ju s t afunction of more individuals reaching middle age andolder in the US population.

    Obesity-related diseases. Obesity is considered a co-m o rb id i ty o f so m e o f th e m o st p re vale n t d ise ase s o fmodern s ociety (26, 40). In fa ct, t he num ber of comorbid-i t ies d isplaye d b y an in d ivid ual r ises with in cre asin gbody w eight (40). For exa mple, a B MI a bove 35 kg/m 2 isassociated with a 93-fold and 42-fold increase in therisk of Type 2 dia betes in w omen a nd m en, respectively.The risk of corona ry h ear t disea se is increased 86%by a20% rise in b o d y w e ig h t in m e n , wh e re as th is r isk is

    increased 3.6-fold in obese women (26). Ahigher preva-lence of diseases such as hypertension, osteoarthritis,an d gallbladder disease is also associat ed with increas-ing obesity (40). Undoubtedly, one of the best publich e al th ap p ro ach e s wo u ld b e to co n ce n trate o n m e a-sures that prevent obesity.

    Aging population. Our population is getting older.Currently, 3.5 million US citizens are 85 yr or older. Aqua rt er of all w omen and 15%of all men over the ag e of84 yr lived in n ur sing h omes in t he 1990s (4). Moreover,there will be a substantial increase in the relative sizeof th e elderly populat ion a fter t he year 2011, when t heoldest m embers of the ba by-boom cohort (people born in1946) r e a c h t h e a g e of 65 y r. Th e C e ns u s B u r e a u

    p ro je cts th at , b y th e ye ar 2040, th e re wil l b e at le ast813 million Americans 85 yr of age of older (4). Thei m p o r t a n c e o f t h e s e s t a t i s t i c s i s t h a t , i n a d d i t i o n t otheir increasing prevalence in our younger population,most chronic diseases are also considered age-relateddiseases, since they clinically ma nifest t hemselves to agrea ter degree lat er in life (40). Thus t he preva lence ofchronic diseases w ill begin to increase dra stica lly wit hinthe next tw o deca des. I t is no secret tha t our health car esystem is headed for deep trouble unless we soon find away to implement better preventive measures againstth e progression of chronic disea ses.

    The P a nel on Scientific B ounda ries for Review a t t heN at ion al I n st i tu te s o f H e alth (N I H) re ce n tly p oste d a

    draft document proposing major changes at the NIHsCenter for Scientifi c Review (43). In t he fir st pa ra gra phof that document, the Panel referred to the stunningsuccesses of the biomedical research enterprise. Weag re e th at th e re h as tru ly b e e n a wid e array o f e xce l-lent resea rch gains ma de by pa st a nd present biomedi-cal scientists. Support for this research should surelycon tin u e. Ho we ver, th e d e fi n it ion of s tu n n in g su c-cesses may depend on the criteria by which we mea-sure success. The lack of knowledge about the biologicalmecha nisms underlying th e ca use of the ma jor increasein chronic diseases in recent decades is classified as a

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    stunning failure by us. In this respect, the focus onselected research fronts may have drawn our attentiona w a y f r om t h e o ve ra l l w a r a g a i n st m od er n ch r on i cdisease. Are w e fully r ising to the cha llenge of fight ingthe chronic disease epidemic, or are we missing oppor-tunities for a victory?

    Only Fi ghting H alf of the Batt le: Bein g Reactive

    I nstead of Pr oacti veIt is understa nda ble tha t ma ny look optimistically at

    th e p rog re ss b ein g m a d e a g ain st ch ron ic d isease . N oone would deny that physicians and biomedical scien-tists have increased the understanding of mechanismsu n d er l y in g t h e t r e a t m e nt of ch r on i c d i sea s e a t a ne xp on e n tial ra te : m e d ical re sear ch h as ad va n ced inw on d er fu l a n d r em a r k a bl e w a y s i n t h e p a s t 75 y r.Ho we ver, m ost b iom e d ical ad va n ce s for ch ro n ic d is-eases have made their great est impa ct after the disea seis clinically observed and diagnosed. Although thesead va n ce s a re e xtre m ely im porta n t for th e m il lion s ofAmericans already suffering from chronic disease, is

    this a ll tha t we ca n do to comba t chronic disea se? Thea bove sta tistics would indica te otherwise.We believe that the current research efforts against

    ch ro n ic d ise ase are in co m p le te in th at th e y fo cu s al-most entirely on secondary and tertiary prevention ofd ise ase ( i .e . , t re atm e n t o f d ise ase af te r i t h as m an i-f es t ed i t s el f). O t h er s h a v e m a d e s i mi la r ca l l s. F ore xam p le , th e e d ito rs o f th e New England Journal of Medicinerecently wrote, Aprogressive fattening of thepopula tion is not inevita ble. We need to do a bet ter jobof educating people about healthful diets, including thecalorie content of common foods, w ithout promotingfetishes. Encouraging lifelong, regular exercise in chil-d r en m a y w e ll h a v e t h e g r e a t e st eff ect i n t e rm s of

    preventing obesity, as well a s numerous other benefi ts.If t he time children now spend in front of th e televisioneat ing junk food and w a tching advert isements for morejunk food was instead spent in physical activity, lean-n es s w o ul d b e v i r t u a l ly e ns u r ed . H e a l t h fu l ea t i n gha bits a nd r egular exercise become even more criticalin yo u n g ad u lth o o d , wh e n a te n d e n cy to ward o b e si tyty pica lly a ppea rs(27).

    We believe we must implement research strategiest h a t a r e a l s o p r o a c t i v e i n a d d i t i o n t o t h o s e t h a t a r ereactive. I t is terribly shortsighted to set th e stan da rdsb y wh ich we ju d g e p ro g re ss ag ain st ch ro n ic d ise aseso le ly with in th e co n te xts o f se co n d ary an d te rt iaryprevention. In contrast, public health workshops have

    p rod u ce d con sen su s sta te m e n ts a ssert in g t h at s tra te -gies aimed a t primary preventionw ill be key to era dicat -ing chronic diseases. We agree with these statementsa n d s ug ges t t h a t t h e c ur r en t w a r a g a i n st ch r on icdisease can be bolstered by expanding our biomedicalresearch efforts into t he litt le explored (and even lesssupported) bat tlefield of prima ry prevention.

    Ou tflank i ng th e E nemy: Pri m ar y Prevent ionof Chr oni c Di sease

    Hea rt tr eat ment gains, but prevention failsw a s thetitle of a September 24, 1998, article in the Houston

    Chronicle. In six words, this sta tement summa rizes thep lig h t of con te m p ora ry b iom e d ical re sear ch ag a in stch ro n ic d isease . S e con d ary an d te rt iary tre at m e n t o p -tions for ma ny chronic diseases ar e increasing, a nd th ei m por t a n c e of t h e r e se a r ch b eh i nd t h e se a d v a n c esca n n o t b e u n d er e st i m a t e d . S t i ll , a r e w e n ot s el li n gourselves short ? Is it enough just t o tr eat th e symptomsan d n ot t h e cau se o r to tre at th e cau se after it precipi-ta tes t he clinica lly overt disease? Conversely, prima ryp reven tion is u n u su al as a m e d icin e in th a t i t isimplemented beforea chronic disea se is clinica lly ma ni-fested. That is, a chronic disease will never reach itsclinical horizon to compromise the health of an indi-v id u a l i f i t i s a t t a ck ed a t i t s or i gi n t o d e la y a n d /orprevent its progression. Prevent ing a chronic disea se int h e fi r s t pl a ce i s m or e h u ma n e a n d p rod uces l es ssuffering tha n tr eat ment /seconda ry prevent ion of overtd ise ase . I t is a lso m u ch le ss e xp e n sive to so cie ty interm s of healt h car e costs. To pra ctice prima ry preven-tion is con sid ere d com m o n se n se in oth e r ar e as ofs oci et y. F or e xa m p le , i s i t n ot l es s d a m a g i n g a n dexpensive for a n a utomobile to undergo routin e maint e-n an ce su ch as o i l ch an g e s rath e r th an to u n d e rg o anen g in e r e pl a cem en t a f t e r s ev er a l y ea r s of n eg le ct ?M ore over, p rim ary p reven tion h as e ve n b ee n u sedsu ccessful ly ag a in st n on ch ro n ic d isease s. P ol io an doth e r in fe ctiou s d isease s h ave b ee n virtu al ly e lim i-nated through the use of primary prevention methods(i.e. , va ccinat ion). I f prima ry prevention ha s been suc-ce ss f ul ly e m pl oy ed i n t h e w a r a g a i n s t t h e se ot h e rd i s e a s e s , w h y n o t u s e t h i s s t r a t e g y a g a i n s t m o d e r nchronic disease?

    TAKING THE BATTLE TO THE ENEMY: ATTACKING THE

    ROOTS OF CHRONIC DISEASE

    Ho w d o we , as b io m e d ical re se arch e rs, in ve stig atep h en om e n a th a t wil l u l t im ate ly le ad t o in terve n tion alstrate g ie s ag ain st ch ro n ic d ise ase at th e le ve l o f p ri-ma ry prevention? To at ta ck the enemy a t it s source, wem u st fi rst u n d e rstan d i t .

    Or i gin s of Ch r onic D isease: Genes Respond in g to anAlt ered En vir onment

    The etiologic foundat ions of most modern chronicdiseases are considered heterogeneous and highly de-pendent on the environment. For instance, only a smallproportion of individuals with coronary heart diseased e ve lo p th e d ise ase p rim ari ly as a re su lt o f a s in g le

    gene defect (e.g., fam ilia l hypercholesterolemia). Infact , th e p re cip itat in g d e fe ct in m o st co ro n ary h e artdisease pat ients ma y be a combinat ion of environmen-t a l f a ct or s t h a t r es ul t i n a cl us t er ed i nci den ce ofoverlapping conditions such a s a therosclerosis, h yper-tension, Type 2 diabetes, hyperinsulinemia, visceralobesity, and elevated triglycerides (sometimes calledthe metabolic syndrome or syndrome X). Likewise,the increa sing preva lence of Type 2 dia betes a nd obe-si ty is n ot d u e to n e w g en e m u ta tion . An in te restin g ,b u t m isle ad in g , s ta te m e n t m a d e b y som e scie n tists istha t genes ar e part ly responsible for t he currently h igh

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    incidence of Type 2 diabetes a nd obesity. It is tr ue tha texisting genes interact with the environment to resultin phenotypic expression of these diseases; however,these sa me scientists fa il to further clarify th e issue bypointing t o one importa nt fact: 100% of the increaseinp revale n ce o f Typ e 2 d ia b ete s an d ob esi ty in th e USd u r in g t h e l a t t e r h a l f o f t h e 2 0t h ce nt u r y m u s t b eat tr ib u te d to a ch an g in g e n viro n m en t in te ractin g with

    genes, since 0% of the hum an genom e h a s c h a n g e dduring t his time period (i.e., no new mut a tions causingthese increased incidences have occurred in this pe-riod). Similarly, the 29-fold increase in heart diseased ea t h s f r om 1900 t o 1996 (3) c ou ld n ot b e d u e t oc h a n g e s i n t h e h u m a n g e n o m e . I n f a c t , E a t o n a n dKonner (13) stated, The human genetic constitutionh as ch an g e d re lat ive ly l i t t le s in ce th e ap p e aran ce o ftru ly m o d e rn h u m an b e in g s, Homo sapiens sapiens,ab o u t 40,000 ye ars ag o . Th e y fu rth e r e m ph asiz e ,Chronic illnesses affecting older, postreproductive per-so n s co u ld h ave h ad l i t t le se le ctive in flu e n ce d u rin gevolution, yet such conditions are now the paramountcause of morbidity and mortality in Western nations. Thus it is some alteration(s) in the environment thatm u s t u lt i m a t e ly b e t h e r oot ca u s e of t h e i n cr ea s e dincidence of modern chronic diseases.

    Discovering theEnvironmental Root(s)of Chr oni c Di sease

    Th e q u estion re m ain s: w h at al te re d e n viron m e n talfactors have elicited the increased incidence of chronicd i se a s e i n t h e 20t h ce nt u r y ? E s t a b l i sh i ng on e t r u ecausa l effect is unlikely. H owever, wha t if one pa rticu-lar e n viro n m e n tal facto r we re id e n tifi e d th at h as b e -com e d ra m at ical ly m ore p ron ou n ce d in th e p ast ce n -tur y? Moreover, wha t if i t were shown tha t reducing the

    m ag n itu d e o f th is e n viro n m e n tal facto r b ack to p re -1900 sta tus could 1) potentially prevent most chronicdiseases before t hey st a rt (i .e. , primar y prevention), 2)p rofou n d ly a n d p osi t ive ly im pact vir tu al ly al l k n ownchronic disease conditions even after their diagnosis, 3)decrease morbidity while increasing longevity and vital-ity in older individuals, 4) im p rove m e n tal h e al th an dsense of w ell-being, a nd 5) ha ve the a bility to decreasea nnua l US healt h care spending by hundr eds of billionsof d ol la r s w h i le cos t i ng l it t l e t o n ot h i n g i n r e t ur n ?Would this altered environmental factor be considereda potential origin of chronic disease(s)? Would the studyof the biological effects of this environmental factor bewo rth y of p u blic fu n d in g ? Wou ld i t b e b e n efi cial to

    d e te rm in e th e e f fe ct o f th is e n viro n m e n tal facto r o ngene expression at a molecula r level?

    S u ch a n e n viron m e n tal factor d oe s e xist : physicalinactivity.

    A re ce n t e d ito rial b y K o p lan an d D ie tz (28) o f th eCenters for Disease Control and Prevention perfectlyd e scrib es h ow p h ysical in activity h as u n fortu n a te lybecome firmly established as part of our environmentan d also e m p h asiz e s th e n e e d fo r at tack in g p h ysicalin activi ty at th e p rim ary p re ve n tio n le ve l . I t s tate s,despite the pervasive conceptual preference for beinglean an d active, th e e n viron m e n ts a n d b e h aviors t h at

    ha ve been developed make both cha ra cterist ics difficultt o a c h i e v e . F a r t o o m a n y p e o p l e a p p e a r t o h a v e a c -cepted t he determina nts of the problems of overweightand inactivity, and rely on treatments in the forms ofmyriad ineffective diet remedies and nostrums. As withma ny hea lth issues, it is essential t o emphasize preven-tion a s t he only effective a nd cost-effective a pproach.

    A MAJ OR BATTLEFRONT: THE FIGHT AGAINST

    PHYSICAL INACTIVITY

    The avera ge amount of huma n da ily physical a ctivityhas declined alarmingly over the past century. It is nowk n o wn th at p h ysical e xe rcise b e n e fi cial ly af fe cts th eh u m an b od y in a m u lti facto rial m an n e r. Ho we ve r, th en u m b e r o f ch ro n ic d ise ase s an d asso ciate d fi n an cialcosts potentia lly produced by physical ina ctivity is st illm u ch larg e r t h an g en e ral ly a p pre ciate d . I n d e e d, w iththe possible exception of diet modification, we know of no single intervention with greater promise than physi-cal exercise to reduce the r isk of virtual ly al l chronicdi seases sim ul tan eously. For exa mple, only a sma ll pa rt

    of this picture w a s elucidat ed by G rundy (21) when hewro te , Ce rta in ly, ob esi ty an d p h ysical in activity areth e d o m in an t cau se s o f in su lin re sistan ce , al th o u g hgenetic fact ors undoubtedly a ffect it s severity. The mosteffective thera pies for insulin resist a nce a re weight lossan d in cre ase d p h ysical act ivi ty . Ef fo rts to ach ie ve adesirable body w eight an d to enhance physical a ctivityare e sse n tial com p on e n ts of p rim ar y p reven tion , inboth public health and clinical arenas. As we addresslate r , a n im porta n t b u t u n d ere m ph asiz e d con cep t isth a t th e cu rre nt h u m an g en om e e xpe cts an d re qu ire shuma ns to be physica lly active for norma l function andh e alth m a in te n an ce.

    Sil ent Epi demi c: M orbi di ty and Mortal i ty of Physical Inactivi ty

    Most prevalent chronic disea ses ha ve an a ssociat ionwith p h ysical in activi ty, a n d a n u m b er of r isk fa ctorsfor ch ron ic d isease s th a t are p recip ita te d b y p h ysicalin activi ty are p re se n te d late r in th is p ap e r. A re p o rtfrom th e C e n ters for D isease Co n trol a n d P re ven tionincluded t he conclusion, P hysical inactivity is one ofthe ma jor underlying causes of prema ture morta lity inthe United States (8). According to Powell and Blair(47), q u a n t i t a t i ve e st i m a t e s i n di ca t e t h a t s ed en t a r yliving is responsible for about one-th ird of deat hs due t ocorona ry hea rt disea se, colon ca ncer, a nd Type 2 diabe-

    te s ( th ree d isease s for wh ich p h ysical in activity is a nestablished primary causal factor). Thus, if everyonew e r e h i g hl y a c t i ve , t h e p r em a t u r e d ea t h r a t e f r omth e se th re e d ise ase s co u ld p re su m ab ly b e o n ly two -thirds of the current ra te.

    A re ce n t p rosp ective stu d y fou n d a s tro n g in verserelationship between an individuals energy expendi-ture and the incidence of coronary heart disease (34).Among women w ho wa lked briskly a t least 3 h/wk orexercised vigorously for 1.5 h/w k, t he r isk of coronar yh e art d isease wa s re d u ce d b y 30 40%. L ike wise, aprospective study of 21,000 physicians found that men

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    w ho exercised enough t o sw eat once per w eek were24% less likely t o develop Type 2 dia betes compa redwith m e n wh o d id n o t e xe rcise . F u rth e rm o re , i f th ef r eq u en cy of e xe rci se w a s 2 4 t i m es p er w e ek , t h eincidence of Type 2 dia betes w a s reduced by 39%. Thebenefits of exercise were most pronounced in the mostobese physicians. The authors concluded that at least25%of th e incidence of Type 2 dia betes ma y be a tt rib-

    uted t o a sedenta ry lifestyle (35). La stly, there are a lsoob esi ty-in d ep en d e nt r isks to sed e n tary l ivin g. Un fi tm e n i n t h e l o w e s t q u a r t i l e o f w a i s t g i r t h h a v e b e e nshown t o have 4.9 times the risk of all-cause morta lityth a n t h e ir p e ers w h o we re fi t (30). I n th is s t u d y, u n fi tm e n with m o d e rate ly h ig h waist c ircu m fe re n ce s h adtw ice the risk of dying tha n fi t men of similar w a ist size.The aut hors concluded tha t fi t men ha ve great er longev-ity t ha n unfi t m en regardless of their body compositionor risk factor st a tu s. Likewise, Wei et a l. (57) a lso foundlow fi tness to be a n independent predictor of a ll-causem o rtal i ty b u t fo u n d th at th e r isk o f d e ath d u e to lo wfi t n es s r i se s f r om a p pr ox im a t e l y t w o fol d g r ea t e r t othr eefold great er a s obesity increases.

    We call the prevalence of inactivity-related chronicdiseases a silent epidemic because, in relation to theother preventable causes of deat h in the Unit ed Sta tes,there has been relatively far less public outcry for morer e se a r ch t o p re ven t p hy s ica l i n a ct i v it y. H a a p a n e n -Niemi et a l . (22) concluded from an epidemiologica lstudy that efforts to increase physical activity deserveas m u ch co n sid e ratio n as th o se aim e d at in flu e n cin gm o re tra d i t ion al r isk facto rs . Ho we ver, th e m e d ia re -p ort n o p olit ical or social act ion g rou p s p rote stin gag a in st p h ysical in activity ; o th e r cau se s of d e ath h aver e ce iv ed m u ch m or e a t t e n t ion a t t h e s oci et a l a n dlegislat ive levels. For insta nce, of th e 2.1 million deat hsi n t h e U S e a ch y ea r , r ou g hl y on e-h a l f r e su lt f r omp reven ta b le cau se s (36). Tab le 1 sh ows th a t at least28%of these prevent a ble dea th s a re due to th e combina-tion of physica l ina ctivity a nd ina ppropria te diet (physi-ological condit ions tha t a re too complexly interw oven tocurrently separate). Although this is an already alarm-i n g s t a t i s t ic, i t i s l i ke ly m u ch h i gh er t h a n t h i s . Wee stim ate th e a n n u al n u m b e r of U S d e at h s f rom p h ysi-c a l i n a c t i v i t y a l o n e t o b e 250,000 (see Ta ble 1 forcalculations). Th is equates to sedenta ry l ivi ng r esul ti ngin nearl y one quart er of al l preventable deaths yearl y inthe US! Yet, it is t ra gica lly ironic tha t m a jor legisla tivea c t i on s h a v e b ee n i m pl em e nt e d t o p r ot e ct s oci et yagainst virtually all other forms of preventable deathsexcept for those resulting from physical inactivity. Ofcourse it would be ludicrous to propose a law mandat-ing that people exercise; however, the low governmen-tal an d so cie tal p re ssu re s ag ain st p h ysical in activi tyare strikingly disproportionate to the obviously largedetrimenta l effects of physica l a ctivity on the hea lth ofU S citizens.

    I n Real i ty, We Study Physical I nacti vi ty andN ot Physical Activi ty

    We propose that todays prevalently sedentary life-s t y l e d i r ect l y con t r a d i ct s on e of t h e n a t u r a l f or ce s

    driving t he evolution of our genes. Tha t is t o say, genes

    require the stimulus of physical activity to promote astate of health. We further propose that exercise biolo-gists (including ourselves) have unintentionally madeless tha n optimal impa ct on society a bout the profoundd an g e rs o f se d e n tary l ivin g b e cau se we m isle ad in g lydesigna te physical ina ctivity, a nd not physical a ctivity,a s th e tra ditiona l contr ol condition in our experimenta ldesigns (explained fur th er in th is section).

    Modern human beingsinherited a genomethat evolvedwi thi n a ph ysical ly active l i festyle. A physically a ctivee xisten ce p re dom in ate d th ro u gh ou t m ost of h u m anhist ory, leading up to an d cont inuing 45,000 yr a fter t he

    Ta ble 1. M ajor causes of year ly p revent able death sin t he U ni ted Stat es by per cent

    C a u s e

    Es t i m a t e dAnnualD e a t hs

    Percenta ge ofPr e v e nt a bl e

    D e a t hs

    S a m p l e of La w san d/or G roups

    Opposing Lifestyle

    Toba cco 400,000 38 An t it oba cco la ws(aga inst advert isingor selling to minors,public smoking,etc.), an titoba ccolobby and la wsuits ,Surgeon Generalsw a r n in g s

    P h y s ic a lina ctivit y/diet

    300, 000* 28* P r e si de nt s C ou n ci l onPhysical Fitness,National C oalit ionfor PromotingPhysical Activity,advert isements forlow-fat or healthfoods

    Alcoh ol 100,000 10 L a ws a ga in st a lcoh olconsum ption byminors, AlcoholicsAnonymous,Mothers AgainstDrunk Drivers

    Micr obia l a gen ts 90,000 8 I mm uniza t ion la w sand drug companies

    Toxic a gen t s 60,000 6 L a ws a ga in st illega lwa ste disposal,En v ir on m e n t a l P r o-tection Agency

    F ir ea r m s 35,000 4 F ir ea r m la w s, guncontrol lobby

    S exua l beh a vior 30,000 2 AID S a ct ivist sMot or veh icles 25,000 2 Mot or veh icle la w s,

    Department ofTra nsporta tion,Department ofPublic Safety

    I llicit use of drugs 20,000 2 D rug la ws, D rugEn forcement Agency

    Information was adapted from Ref. 36. *We believe these numbersunderest imate the number of deaths due to physical inact ivity andpoor diet . After McGinnis and Foege (36) published t heir s t udy,Powell and Blair (47) reported that quantita t ive est imates indicatethat sedentary living is responsible for about one-third of deaths dueto coronary hear t disea se, colon cancer, and Type 2 diabet es. [52%oft h e 9 5 9 , 2 2 7 d e a t h s d u e t o c a r d iov a s c u la r d is e a s e a r e c a u s e d b ycoronary heart disease a nd a therosclerosis498,798 deaths (Ameri-can Heart Associat ion)193,000 deaths due to diabetes (AmericanDiabetes Association)56,600 death s due t o colon cancer (AmericanCancer Society)] 3 249,217 deat hs solely due to sedenta ry living ,independent of poor diet.

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    emergence of the modern human genome (i.e. , H o m o sapiens sapiens) (13). A hunt er-ga th erer (noma dic) a ndp er h a p s e q ua l l y a c t i ve a g r a r i a n s oci et y d om i na t edd u r in g t h a t t i m e, on l y c h a n g in g r ecen t l y w i t h t h eb eg in n in g of th e in d u stria l re volu tion , a l it t le m oreth a n 100 yr ag o (13). Co n ve rsely, in in d u strial iz eds oci et i es t od a y, w e h a v e com e t o a p oi n t i n h u m a nhistory a t w hich occupa tions demanding much physicallab or are ra re a n d g e n era l ly re stricte d o n ly t o you n g ,u n e du cat e d m a les. Ou r an ce sto rs t h e refore l ived an devolved in a much more physically demanding environ-ment than is seen in current industrialized societies.More evidence for this statement comes from recordeda c t i v it y l ev el s of r e m a i n in g con t e m por a r y h u n t e r-ga therer/agr ar ian societies. F or just one exa mple, a1978 stu d y o f th e M a ch ig u en g a I n d ian s in P e ru re -v ea l ed a n a v er a ge en er gy expen dit u re of 60k c a l k g1 d a y1 for Machiguenga men compared witha v a l u e of 3 9 k ca l k g1 d a y1 for US men (39). Thisre pre sen ts a s ta g g erin g 35% d e cre ase in in d ivid ualenergy turnover potentially resulting from industrial-

    ization of society (

    1,600 kcal/da y or 167 lb. of bodyfat /yr for a 75-kg individua l)! Obesity wa s probablynonexistent in a ncient h unter-ga therer a nd/or a gra r-ian societies a s it is for the Ma chiguenga I ndian s toda y.Moreover, in a review by Eaton and Konner (13), it wassh o wn th at ch ro n ic d ise ase s su ch as co ro n ary h e artd isease , h yp erte n sion , d iab e tes, an d som e form s ofcan cer ar e a lso virtu a l ly u n k n own in con te m p orar yh u n te r-g at h e rer societie s, e ven in th o se in d ivid ualso v e r 6 0 y r o f a g e . T h e s e fi n d i n g s i n d i c a t e t h a t t h eincreased prevalence of chronic diseases in industria l-ized societies ma y be an ina ctivity -rela ted phenomenona n d a l s o a r g u e a g a i n s t t h o s e w h o w o u l d c l a i m t h a tchronic diseases a re on the rise solely beca use people

    a re now living longer.We contend tha t the high degree of physical ina ctiv-ity seen in current indust ria lized societies is prima rilya tt ributa ble to technologica l adva nces tha t ha ve great lyl es s en ed t h e n ee d f or p h ys ica l l a b or ov er t h e p a s tcentury. Such a society directly differs from that of ouran ce sto rs in th at we m u st u su al ly sch e d u le e xe rcisein to o u r d ai ly ro u tin e i f an y p h ysical act ivi ty is to b eexperienced. This is in st a rk contr a st to nonindustria l-ized societies like tha t of the Machiguenga India ns, inwh ich both men a nd women work at physically dema nd-ing tasks (i .e. , hunting, farming, traveling by foot) anave rag e of 8 .5 9.5 h /d ay (39). Th e m od e rn h u m ang en om e h a s a h i gh l y c on s er v ed a b i li t y t o a d a p t t o

    extreme a mounts of energy expenditure, a s evidencedby S candina vian lumberjacks, wh o have been reportedt o ea t u p t o 6,000 kcal/da y wit hout ga ining bodyw eight (33). How ever, caloric turnover for a vera ge meni n a n i n du s t r ia l i zed s oci et y i n t h e e a r l y 1 980s w a sestima ted to be only between 2,0003,000 kca l/da y(41). U nfort una tely, a n updat e of Hea lthy P eople 2000for the US Centers for Disease Control and Preventions t a t ed t h a t t h e p r op or t i on of t h e t ot a l p op ul a t i onreporting physical a ctivity fi ve or more times per w eekw a s 23% a n d t h a t t h er e w a s n o t r en d t ow a r d t h eta rg e t g oal of 30% b y ye ar 2000. F u rth e rm ore , t h e

    p ercen ta g e o f 9th to 12th g rad e rs u n d erg oin g d a i lyphysica l educat ion in US schools ha s declined from 42%to 27% (19911997) (7)! An article in the August 18,1999, Houston Chroniclefu rth e r re fle cts th e fact th atphysical work has been and continues to be technologi-cally engineered out of the American lifestyle. It states,Ima gine mow ing the la w n in y our sleep. The ultima telazy persons lawnmowera 15-pound contraption thatdoes the job automaticallyshould be available in theU S early next year. The S wedish-built Auto-Mower,which will come in battery-operated and solar-poweredm od e ls is a h i t a t t h is year s Ha rd wa re S h ow, d rawin gc r o w d s w h o w a n t a p e e k a t w h a t s o m e h o p e i s t h eha nds-free future of law n care. Nobody w a nts to work,so it w ill sell sa id B a rt Colenbra nder of Toront o. Ourconcern is that, while technology has engineered physi-cal lab o r o u t o f th e l i fe style s o f ave rag e US ci t iz e n s,some individuals are proposing to engineer studies ofthe biology of physical inactivity out of the NIH.

    Chronic i nact iv i ty is physio logical ly abnorm al . Webelieve that human bodies fail to function properly to

    ma inta in hea lth in ma ny different w a ys when there is al os s of a d e q u a t e a m o u n t s (h i s t or i ca l l y n or m a l amounts) of physical activity. In other words, our genesexpect t he body t o be in a physica lly a ctive stat e if theyare to function normally. In evolutionary terms, inactiv-i ty e lici ts an ab n o rm al p h en otyp ic e xpre ssion of ou rgenes. Evidence for th is belief comes from observa tionst h a t m os t ch r on i c d is ea s e s a r e n o t a s p r ev a l en t i nsocieties where physical w ork is a la rge part of da ily life(i.e., Mexicans compared with Mexican-Americans) asw e ll a s t h e f a ct t h a t ch r on i c d i se a s e p r og r es s ion i sprevented or d ela yed by the r eintroduction of physica lexercise into populations w here physica l ina ctivity ha sbecome the norm. As biologists studying the molecular

    and biochemical bases of exercise, we further believetha t w e have been viewing research on physica l activityi n t h e w r o n g m a n n e r w h e n w e c l a i m t h a t w e a r estudy ing the effects of physical a ctivity. We submitt h a t i t w ou ld b e m or e a c cu r a t e t o s t a t e t h a t w e a r estudying the effects of physical inactivi ty. In otherwo rd s, b e cau se b ein g sed e n tary is a p h ysiolog ical lyab n o rm al s tate , i t is f ro m a p o p u lat io n o f se d e n taryindividuals tha t t he true experimental group should bet a k e n . Th e con t r ol s a m p le s h ou ld b e t a k en f r om ap h ysical ly act ive p o p u lat io n in ste ad o f th e cu rre n tlyused sedentar y population. Support for this concept ise ve n se e n in cag ed e xp erim en ta l rod e n ts , w h o w il lna tur a lly exercise3 h/da y if given a ccess to a runn ing

    wh eel (23). Therefore, we ha ve suggested (23) tha t,beca use running w a s entirely volunta ry, one could a lsol og ica l l y con cl ud e t h a t t h e se ot h e r w i se a c t i ve r a t simposed with a n inact ive lifesty le (a rt ifi cial ca ge restr ic-tion) are mistakenly called control animals in moste xp erim en ts. Ca g ed an im a ls sh o u ld b e lab e le d a s th ephysically inactive experimental group,and any exer-cise p rog ram d e sig n ed for th e se a n im als sh ou ld b ecalled rehabilitative exercise. In this regard, it mayeven be more a ccura te to sta te tha t w e a re studying theeffect of reintr oducing exercise into a n unh ealt hy seden-t a r y p op ul a t i on t h a t i s g en et i ca l l y p r og r a m m e d t o

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    expect physical activity. Normal functioning of thesean im als g e n e s is with in an e n viro n m e n t o f p h ysicalactivi ty ; cag in g p rod u ce s ab n o rm al g en e e xp ression ,which predisposes animals to modern chronic disease.

    Fal se ster eotype of exer cise physiology. An activelifestyle is associated with a dramatically reduced riskfor ma ny chronic diseases. Appropriat ely performedp h ysical act ivi ty can d e lay, an d in so m e case s e ve n

    prevent, ear ly deat h a nd/or the need for drugs, as sist ed-l ivin g care , h osp ita l iz at ion , or oth e r h e al th care b u r-dens. Yet, despite these obvious public health implica-tions, biomedica l exercise research a s a via ble disciplinein te gra l to p reven tive m e d icin e m a y b e u n d e rem p h a-sized. Why? P a rt of the problem ma y be t ha t exercisephysiology is often perceived by medical scientists tobe a field that exclusively studies elite athletes. Sportsm e d icin e re fe rs to tre at m e n t an d re h ab ili tat ion ofsport s-relat ed injuries, genera lly orthopedic in n a ture.Furthermore, as exercise physiologists, we ourselvesma y be unw itt ingly contributing to the false notion tha twe study only physical training in athletes by purport-ing, as mentioned above, to study the effects of physi-cal activity instea d of the effects of physica l ina ctiv-ity. In other words, a n exercise physiologists typicale xp erim en ta l con d it ion (p h ysical act ivi ty) d oe s n otcon n ot e t h e s t a t e of h ea l t h . Wh er e a s ot h e r h ea l t h -relat ed resea rch fields designat e a physiologica lly abnor-mal (i.e., disease) condition as the experimental group,exercise physiologists define the physiologically abnor-ma l condition (physica l inact ivity ) a s th e control group.The genera l ta ke-home m essage of m ost scientifi cstudies is more highly associated with the experimen-tal co n d it io n with in th e stu d y. F o r e xam p le , s tat in gthat physical inactivity increases your risk of prema-tu re d eat h h as g re at e r pu b lic im pact t h an st at in g th atp h ysical act ivi ty d e cre ase s yo ur r isk of p rem a tu red e ath . Th u s we b elie ve th a t ou r e xp erim en ta l ap -proa ch to physica l activity ha s unfortun a tely detra ctedf r om t h e f a ct t h a t t h e m a j or i t y of e xe r ci se -r el a t e dre se arch is actu al ly h e al th o rie n te d an d n o t p e rfo r-ma nce oriented. We must emphasizeth e fact that physi- ca l act iv i ty induces a gene expression pattern that pr im ar il y pr omotes healt h; secondar y to thi s effect is th ecoincidencethat this geneexpression also concomitantlyser ves to enh ance physi cal per form ance.

    M olecul ar L ink s to Di sease H ave I mpact

    Alth ough st riking epidemiological evidence supportsth e con te n tion th a t se de n tary l ivin g is e xtre m ely u n -

    healthy, we believe it is also imperative to determinethe underlying biologica l mechanisms by w hich physi-cal in a ctivi ty p rom o tes d isease . We con te n d th a t th ee stab l ish m e n t of m olecular l in k s is re qu ired to con -vince for-profi t industries a nd la wm a kers to implementchanges a nd th us promote physica l activity, diet m odifi -cation, or any other primary prevention interventionsag a in st ch ro n ic d ise ase . Th is b el ief is n ot with o u thistorical precedence. For instance, Denissenko et al .(10) provided a direct m olecular lin k betw een a defi nedcig are tte sm o k e carcin o g e n an d h u m an can ce r m u ta-tion s in 1996. B e fore th a t t im e , t ob acco com p an ie s

    claim e d th a t th e re w as n o scie n tifi c e vide n ce l in k in gcancer to tobacco use. Shortly after Denissenko et al .(10) published their results, tobacco companies begano ffe rin g se tt le m e n ts in n u m e ro u s lawsu its b e g u n b ys t a t e s s u ch a s M in n es ot a t h a t w e re a t t e m pt i ng t orecoup health care expenditures for smoking-induceddiseases (49). More restrictive antismoking legislationwa s a lso p asse d in m a n y sta te s. We in terp ret t h is asevidence th a t science can a lter t he behavior of for-profitindustries and lawmakers. We speculate that determi-nation of molecular links between physical inactivitya nd disease might ha ve a similar positive impact on thepolicies of research funding agencies, health care profes-sion als , com p an ies, an d th e g ove rn m en t. I d e al ly, th ee n d re su lt wo u ld b e th at p h ysical act ivi ty b e co m e s ag r ea t e r p a r t of t h e Am er i ca n l if es t y l e. I n s h or t , w ea gree with K oplan a nd D ietz (28) wh en they w rite, Int h e pa s t 25 y ea r s , s ev er a l n ew e r a r e a s h a v e b e enin co rp o rate d as targ e ts fo r c l in ical an d p u b lic h e al thconcern, such as tobacco control and injury prevention.It is now time to promote weight control and physical

    activity.The NIHs Panel on Scientific Boundaries for Reviewalso believes that biologically mechanistic research isi n her e nt l y l in k ed t o ov er a l l h ea l t h , s t a t i n g i n t h e irrecent draft document (43) that The overarching mis-s ion of N I H t o i m p r ov e h u m a n h ea l t h w i l l b e b e stserved by reviewing clinically relevant science in thecontext of the ba sic know ledge on w hich it is founded,an d b y re vie win g b asic scie n ce in th e co n te xt o f th ehuman condition that it is designed to improve. I t isalso ap p are n t f rom th is s tat e m en t th a t th is N I H P an e lplaces high import a nce on viewing a r esear ch field fromthe ba sic to the a pplied level a nd vice versa . Is currentr es ea r c h i n t h e fi e l d of p hy s ica l i n a ct i v it y m ee t in g

    t h e se s t a n d a r d s s et f or t h b y t h i s N I H P a n el a n d a l soidentifying molecular links to whole body health neces-s a r y t o b r in g a b ou t s oci et a l ch a n g e? Th e a n s w e r i syes. Seventeen unhealt hy conditions produced byphysica l ina ctivity were identified from peer-reviewedlitera tur e (Ta ble 2). An exam ple of th e novel biologicalmecha nisms ut ilized by physical ina ctivity for some ofth ese conditions a re included in the next section.

    Smal l Victori es: L im it ed Bu t Pr omisin g Resear ch onthe Bi ology of Physical I nactivi ty

    Tab le 2 i l lu stra te s th a t p h ysical in activity p ote n ti-a t e s a t l e a s t 1 7 u n h e a l t h y c o n d i t i o n s a t t h e c o s t o f

    nearly $1 tr illion/yr. B eca use t he C enters for DiseaseCo n trol an d P re ven tion h as con clu d ed th a t p h ysicali n a ct i v it y i s on e of t h e m a j or u n d er l y in g ca u s e s ofp re m a t u r e m o r t a l i t y i n t h e U n i t e d S t a t e s (8), i t i sim pe rative to d e ve lop th e b iolog ical m e ch an ism s b ywh ich physical inactivity elicits such a powerful effect.In this respect, the biological mechanisms underlyingthe effects of physical ina ctivity a nd exercise interven-t i on s on ch r on i c d i s ea s e s a r e ju s t b eg in n in g t o b eunderstood. Many remarkable and novel observationsare being produced in the emerging field of exerciseb iol og y. I n t e r m s of r e du ce d h u m a n s u ff er i n g a n d

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    h e alth care costs , th e p o ten tial in vestm e n t re tu rn onfunding this field is enormous. Below, we highlight justa f ew s peci fi c e xa m p l es of t h e p r om i si n g r e se a r choccurring in this area. As previously emphasized, theg e n e s a c t i v a t e d b y p h y s i c a l a c t i v i t y t h a t l e a d t o i n -crease d h e al th ar e also coin cid en ta l ly b en e fi cial fore xe rcise p e rform a n ce a d ap ta t ion s. Th e fi n d in g s d e -scribed below a lso underscore th e fact t ha t it is overlysimplistic to think the war against chronic disease canb e w on b y sim ply g ett in g m ore p eop le to d o so m e

    exercise wh en we do not ha ve a solid understa nding ofth e altern a tive biological mecha nisms underlying differ-ent a mounts a nd t ypes of exercise. Most individua ls into d ays in d u strial iz e d so cie ty wan t to sp e n d as l i t t letime and effort exercising as is needed for their indi-vidual healt h concerns. Knowing how exercise mecha -n ism s wo rk wil l b e im p o rtan t fo r d isco ve ry o f wayspeople ca n exercise with little effort a nd t he most ga inin health.

    On e e xcit in g e xam p le of cu rre n tly p rom isin g re -search is t he investigat ion of molecular mecha nisms bywhich physical activity increases skeletal muscle glu-

    cos e u pt a k e a n d i n su li n s en s it i v it y. Th i s h a s h i ghimpact because many of the chronic diseases listed inTa ble 2 ha ve decreas ed glucose upt a ke (i.e., hyperg lyce-m ia an d in su lin re sistan ce) as a com m o n sym p tom .V e ry n o ve l an d u n e xp e cte d fi n d in g s h ave arise n as aresult of exercise st udies on glucose upta ke an d insulinsign al in g p ath w ay s. I n b rief 1) the glucose t ra nsport erG LU T-4 increases in the pla sma membra ne of skeletalmuscle independent of insulin during exercise (19), 2)insulin a nd exercise recruit G LU T-4 from t w o distinctin trace llu lar s to rag e si te s in sk eleta l m u scle (9), 3)insulin-st imula ted tr a nslocat ion of G LU T-4 in skeleta lm u scle in volves m a n y p rote in s (in clu d in g th e G TPbinding protein Ra b4) th a t a re not involved in exercise-stim ula ted G LU T-4 tra nsloca tion (52), 4) insulin sensi-tivity is enhanced postexercise but does not employ theinsulin receptor or insulin receptor substrate (it likelym ay b e re g u late d b y a co m b in atio n o f se ru m facto rs,a utocrine/pa ra crine mecha nisms, a nd mus cle glycogenconcentr at ions) (19), a nd 5) p h ysical in activity p ro-d u ce s i n su li n r es is t a n c e i n s ke le t a l m u s cl e w i t h i n

    hours (51). These and other observations emphasizeth e u n iqu en e ss of s ig n al in g pat h wa ys a ct ivat e d with incontr a cting skeleta l muscle.

    Tw o potent ial clinica l impacts from the distinct signa l-in g m e ch an ism s b etw e en in su lin a n d e xe rcise h aveb ee n sta te d in a re ce n t re vie w b y G ood ye ar a n d K a h n(19). First, exercise does increase insulin sensitivity.However, it is also likely that exercise can function toactivate al te rn ative m e ch an ism s to im p ro ve sk e le talmuscle glucose upta ke in diabetic individuals w ho ar einsulin resistant. Complete elucidation of these alterna-tive sig n al in g m o le cu les in volved in th e e xe rcise-induced activation of glucose transport will be impor-t a n t , a s t h e se p r ot e in s a r e p ot e n t ia l s it e s f or f ut u r epharmacological intervention. Thus research into them e ch an ism s b y wh ich th e wh o le o rg an ism m ain tain sin su lin se n si t ivi ty is im p o rtan t in u n d e rstan d in g th eetiology, prevention, and t rea tm ent of th e chronic meta -bolic syndrome disea ses.

    Oth er exa mples of the complexity of gene expressionat multiple levels (e.g. , pretranslational, translational,or posttra nslat iona l) in response to physica l inactivity/activity further illustrate the impact of exercise biologyresearch. Evidence indica tes th a t exercise ca n regulat ea disease-relat ed gene, like lipoprotein lipase (LPL ; ace n tral d e term in an t of p lasm a l ip op rote in m e ta b o-l ism ), b y m ore th a n on e b iolog ical m e ch an ism . F o r

    in stan ce, th e e n zym e activi ty, p rote in con ce n trat ion ,a n d m R NA c on cen t r a t i on of L P L w e re a l l 2. 5- t o3.0-fold higher in t he fa st-tw itch rectus femoris muscleso f r a t s a l l o w e d t o e x e r c i s e a d l i b i t u m o n v o l u n t a r yrunning w heels for 2 wk compar ed with ra ts r estrictedto t ypical cage confi nement a ctivities (norma l exercisepat tern for runners wa s numerous short, intense boutsa mounting to a t ota l of3 h/da y) (23). The r egula t ion ofL P L a ct iv it y w i t h t h a t t y pe a n d v olu me of h ig h-in te n si ty act ivi ty is th e re fore a p par e n tly a re su lt ofp retra n slat io n al m e ch an ism s. F u rt h e rm ore , i t m a y b especific only to fast -tw itch (nonpostur a l)skeleta l muscle,

    Ta ble 2. Unhealthy conditions precipitatedby physical in acti vi ty and result in ghealth care costs in t he U nit ed States

    U nhe a l t hy C o ndi t io n

    S a m p l eEpidemiological

    Reference(s)

    Annual Cost ofCondition in US

    (US dollars)

    H yper tr igly cer idem ia 17

    H yper ch olest er olem ia 12H yper glycem ia 18I nsulin r esist a n ce 25I ncr ea sed t hr om bosis 14Increased resting blood

    pr essur e 20 $286.5 billionIncreased risk of myo-

    ca r dia l isch em ia 53Increa sed incidence of

    lethal ventriculara r r h y t h m ia s 56

    Decreased cardia cstroke volume a ndm a x im a l c a r d ia cout put 50

    Obesit y 45, 48 $238 billionType 2 dia bet es 44 $98 billion

    B r ea s t a n d col on ca n cer 37, 59 $107 billion for a ll can -cersOst eopor osis 58 $6 billion

    S a r copen ia 5$300 billion for all dis-

    abilit iesB a ck pa in 6 $28 billionG a llst on e disea se 31 $5 billionDecreased psychological

    w ell-bein g 15 (cost n ot kn ow n )

    There ma y be overlap a mong some reported un healthy condit ionswith regard to cost , overt disease classificat ion, and possibly withregard to biological mechanisms. However, we lis t each condit ionseparately because a diagnosable disease does not necessarily ma ni-fest all predisposing conditions simultaneously. Furthermore, due tothe dist inct iveness of each cited reference, it wa s necessary t o a llowt h is ov e r la p t o a v oi d e x c lu d in g a n y on e u n h e a l t h y c on d it ion . A l-though the t otal est imat ed costs of health car e expenses in this ta bleadd to a lmost $1.07 trillion, this total may approach, but would notlikely exceed, $1 trillion after elimination of overlapping comorbidi-ties.

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    since differences were not present in the slow-twitch(post ura l) soleus m uscle or a dipose tiss ue (23). Altern a -tively, w ithin severa l hours of hindlimb immobilizat ion,L P L a ctivi ty is g re atly re d u ce d in b o th th e soleu s a n drectus femoris muscles independent of any change inLP L mRNA or protein concentr a tion (M. T. H a milton,unpublished observa tions). This indicat es t ha t post-tr a nslat iona l mecha nisms ma y be affected in both slow-

    an d fast- twitch m u scle s b y th e re m o val o f e ve n th es m a l l a m o un t s of p hy s ica l a c t i vi t y a s s oci a t e d w i t he veryd a y we ig h t-b ear in g a ct ivi t ies in a cag e e n viron -m e n t. T h u s th e m e ch an ism s b y wh ich e ve n a s in g legene (e.g. , LP L) responds to va rious forms of exercisea nd/or physica l inact ivity a ppar ently depend on 1) th ety pe of t he skeleta l muscle studied; 2) the ty pe, inten-sity, and dura tion of physical a ctivity/inactivity; a nd 3)th e level of gene expression st udied. These fi ndings a rean example of how exercise biology research may pointto ward th e d isco ve ry o f al te rn ative m e ch an ism s fo rregulating LPL (and other genes)that determine plasmalipoprotein meta bolism a nd susceptibility t o a th eroscle-rosis.

    Another exa mple of biologica lly mecha nist ic researchin th e fi e ld of p h ysical act ivi ty/in activity re lat e s t ocontr a ctile proteins in skeleta l muscle. Tra nslat iona lincreases in protein synthesis preceded any increasesin rRNA in hypertrophying skeletal muscle (29). Like-wise , tran slat io n al re d u ctio n s in m yo fi b ri l lar p ro te insyn th e sis p re ce d e d an y re d u ctio n in sk e le tal -actina n d m y os in h ea v y ch a i n m R NAs w h en l oa d i ng ofskeletal muscle was reduced (54). These latter findingsare p art icu larly im p o rtan t wh e n we co n sid e r th at th ea nnua l costs of disabilities, to a la rge extent includingskeletal muscle atrophy (sarcopenia), approach $300bill ion (see Ta ble 2).

    CALLING FOR REINFORCEMENTS

    C u r r en t l y, t h e r e i s n o m a j or N I H i n it i a t i v e t h a tencourages biomedical researchers to study the biologyof the primary prevention of chronic diseases. In fact,the significan ce of a research gr a nt proposa l likelycarries a grea ter w eight with r eviewers if it is designedto stu d y m e ch an ism s u n d erlyin g a preexistingdiseasesta te, wit h th e results of this research being applied ina se co n d ary o r te rt iary fash io n . Ho we ve r, th e p o te n -tially enormous return of investing in the prevention ofdisease on th e primar y level ca nnot be oversta ted. Wetherefore issue a challenge to the NIH a s w ell a s otherpublic and privat e funding agencies: establish a major

    in i t ia t ive dedicated to support ing and prom oting thein vesti gation of biological mechani sms l eadin g t o pri - m ar y prevent ion of chr onic di sease.

    War B onds: A Sound I nvestment i n the Fut ur eof US H ealth Car e

    Investing in the primary prevention of chronic dis-eases is not just a n opportun ity but a lso a necessity forth e N I H. F o r in stan ce , re se arch in to th e d e trim e n taleffects of physica l inactivity a nd ina ppropriat e diet a reju st two o f m an y are as th at wo u ld b e in clu d e d in th e

    area of primary preventive medicine. The combinationo f th e se two u n h e alth y b e h avio rs is e st im ate d to ac-count for at lea st a n estima ted 28%(a nd probably more;s ee Ta b le 1) of a l l pr ev en t a b le d ea t h s i n t h e U Sa nnua lly (14%of tota l deat hs). Even w ith t he use of thelower va lue that results from lumping preventable an dunpreventable mortality together, a quick calculationof 14% of the $13 billion a nnua l NIH tota l opera tingbudget leads to a fi gure of over $1.8 billion. Therefore,as a percentage of the NIHs total budget, the combinedmortality of physical inactivity and inappropriate dieta l on e i s eq u i va l e nt t o t h e cos t s iz e o f t w o N I Hi n s t i t u t e s ! A l t h o u g h w e r e a l i z e t h a t n o t a l l N I H r e -s ea r c h f u nd i ng i s d ir ect l y d ed ica t e d t o p r ev en t i n gd ea t h , s im il a r fi g u r es a r i se w h en w e con s id er t h efunding th a t should be a llocat ed to reducing the morbid-ity of chronic disea ses. In Ta ble 2, t he t otal cost of the17 condit ions predisposed by phy sical ina ctivity is closeto a t rillion dollars per year (a ctual fi gures add t o overon e t r i ll ion d ol la r s , b u t t h e r e i s s om e ov er l a p f orcomorbidities). However, we estimate that NIH annu-

    a l l y s pen d s l es s t h a n $10 m i ll ion t o d et e r m in e t h eu n d e rlyin g m e ch an ism s b y wh ich p h ysical in activi tyincreases t he risk of chronic disea ses. This mea ns t ha t0.08% of t he NIH budget is currently a llocated form ech a n i s t ic s t u d ies i n t o t h e u n h ea l t h y ef fe ct s of asedenta ry lifestyle!

    To continue invest ing a lmost exclusively in resea rchth a t in vestig ate s th e secon d ary a n d te rt iary t re atm e n tof ch ron ic d isease s is e xtre m e ly sh ortsig h te d . Th ehealth care industry is paradoxical in that its principalg o a l s h o u l d b e t o e n d h e a l t h p r o b l e m s a n d h u m a nsu ffe rin g in an at te m p t to p u t i tse l f o u t o f b u sin e ss.Wh e re as fu n d in g su p p o rt fo r se co n d ary an d te rt iaryp re ve n tio n is vi tal to th e 90 million Americans al-

    ready plagued by chronic disease, an unfortunate sideeffect of the present system is that it actually enablesa n increase in disease preva lence by not preventing itin th e fir st pla ce. In rea lity, less money w ould be neededfor research into secondary a nd tertia ry tr eat ments of adisease if we prevent it from occurring at all . Currentresearch ga ins ha ve not been successful in preventingchronic disea se, and there is no end in sight. Indeed, asshown ear lier in t his review, using public health a s th efi n a l o u t c o m e m e a s u r e , p r o g r e s s i n t h e w a r a g a i n s tch ro n ic d ise ase is larg e ly a s tu n n in g fai lu re. A n e wap p roach m u st b e fou n d . I f fu n d in g ag e n cies su ch asth e N I H in vest in m e ch an ist ic b iom e d ical re searchdesigned to trea t chronic disease on t he secondary a nd

    t er t ia r y l ev el , i s i t n ot , a t t h e v e ry l ea s t , eq u a l lyim porta n t to in vest in s im ilar re search d esig n ed toprevent chronic disease at the primary level? Likewise,beca use t hese a gencies a ctively support biologica llym e ch an ist ic a g in g re search to in crease lon g evity an dquality of life in the elderly, is it not logical to supportbiologica lly mechanistic resear ch, the goal of which isto lay th e fo u n d atio n fo r su ch b e n e fi ts far b e fo re anaging person becomes sick, disabled, or frail? Would itbe of interest t o an individual to ut ilize the benefit s ofprimar y prevention resear ch as a n investment in his orher persona l futur e? Of course it would. In effect, this

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    cou ld b e cal le d l ife in su ran ce t h at b ecom e s activebefore one dies.F ina lly, w hen one speaks of preventingdisease in our society, it usua lly brings t o mind ima gesof preventing infectious disea ses. I t is impera tive tha tw e s t a r t t h in ki ng of ch r on ic d is ea s e i n t h e s a m efash ion. To ignore t his fa ct is to do a n extreme disser-v ice t o t h e A me r ica n p ub li c a s w e ll a s t h e w o r ld spopulation in general.

    F ir ing M agic Bul lets at the Enem y

    Wh y is i t im p o rtan t fo r re se arch in to th e p rim aryprevention of chronic disease to be biologically mecha-n is t ic? S om e i nd iv id ua l s m a y a r g u e t h a t i t i s n oti m por t a n t t o k n ow t h e m ech a n i s m s u n d er l y in g t h em e th od b y wh ich p h ysical in activity or in ap prop riat ediet lea d to chronic disease, only tha t w e know tha t w esh o u ld avo id th e se u n h e alth y h ab its . I n o th e r wo rd s,b ecau se we a lread y k n ow th a t e xe rcisin g o r ch an g in gd i et a r y h a b i t s c a n b e b en efi c ia l t o h e a l t h , s om e m a yb elie ve th a t ju st te l lin g p eop le to im plem e n t su chlifestyle cha nges is enough. However, this is not enough

    for several reasons! First , on the ba sis of our previouse xam p le o f d irectly l in k in g t ob acco t o can cer on amolecular basis, determining biologically mechanisticl in k s b e twe e n l i fe style h ab its an d ch ro n ic d ise ase isimporta nt t o pressure for chan ge at t he legislative an dindust ria l levels. Agood exam ple of th is phenomenon ist h e f a c t t h a t k now n t ob a cco u s e n ow r es ul t s i n a nin cre ase in an in d ivid u al s h e al th an d l i fe in su ran cepremiums. However, insura nce compa nies ra rely ra isepremiums based purely on the fact that their client isina ctive or eat s poorly.

    Second, the determinat ion of biologica l m echa nismsis importa nt to define t he precise varia tions of physica la ctivity a nd/or diet m odifi cation tha t r esult in the most

    desired effects on targeted risk factors. Most researchinto the effects of primary prevention of chronic dis-e ase s m u st u se e stab l ish ed risk facto rs for th e se d is-e a s e s a s a n i m m e d i a t e o u t c o m e m e a s u r e t o t e s t t h ee ffect of an y in te rve n tion . B e cau se t h e se r isk fa ctorsa re modified on t he molecula r t o the w hole body level,mechanistic research is required to identify the exactphenomena involved in such processes to optimize thechoice of interventional variables. Researchers study-ing t he effects of physical ina ctivity a re just beginningto elucidate the biological mechanisms by which vary-ing an exercise stimulus can distinctly target differentchronic disea se risk fa ctors. F or insta nce, it is excitingan d p ro m isin g fo r th e fu tu re to d ist in g u ish th e p ath -

    w a ys by w hich lack of aerobic a ctivity more potentia tesconditions such as coronary heart disease a nd obesity,wh e re as lack o f re sistan ce act ivi ty m o re p o te n tiate sconditions such a s osteoporosis and sa rcopenia. Fur ther-more, as previously summa rized for t he LP L gene, thetype, duration, and intensity of physical activity reintro-d u ce d to a se de n tary an im a l can e ve n af fect m u ltipleexpression levels of a single gene differentia lly. U nder-s t a n d i n g t h e b i och e m ica l , m ol ec ul a r , a n d ce ll u la rm e ch a n i s m s of p hy s ica l i n a ct i v it y w i l l p rov id e t h escientifi c founda tion for a ppropriat e individual prescrip-tion of physical activity for health. Even biologically

    m e ch an ist ic re search in to t h e d e trim en ta l e ffects oftoba cco use does not show such promise for ind ividua l-iz in g p rescription s for p rim ar y p reven tive in te rven -tion!

    Another important reason to support the investiga-tion of biologica l mecha nisms leading t o prima ry preven-tio n o f ch ro n ic d ise ase is th e re al iz at io n th at n o t al lpeople will cha nge their lifestyle no mat ter h ow much

    they a re encoura ged. This trend is a lready evident, a ndit ma y be unrealistic t o expect it to chan ge. Moreover,individuals who are disabled due to paralysis or otherprohibitive conditions cannot change t heir lifestyle a sfar as physical activity is concerned. Finally, there arem an y in d ivid uals wh o e xercise d e vou tly t h at m ay n otb e re ce ivin g th e fu l l b e n e fi ts o f p h ysical act ivi ty b e -caus e of non-exercise-responsive polymorphism s in th eirg en es . A s i mi la r s it u a t i on s ee ms t o e xi st f or d i etmodificat ion. Appropriat ely performed exercise ha s beencalled a ma gic bulletbecause of its a bility t o positivelyimpa ct so ma ny risk fa ctors for chronic disea se, preventa n d d e l a y t h e o n s e t o f t h e s e d i s e a s e s , a n d e n h a n c elongevity a nd q ua lity of life (see Ta ble 2). We a re oftenask e d b y o th e r scie n tists an d lay p e rso n s al ik e wh e nt h e y a r e g oi n g t o m a k e a p il l s o t h a t e xer ci se i sunnecessary. Unfortunately, it is unlikely that a pillwill be developed that results in the vast and complexn u m b e r o f h e al th b e n e fi ts e l ici te d b y e xe rcise wh ilea voiding potentia lly da ngerous a dverse effects. This ison e r ea s o n t h a t e xer ci se b iol og is t s a r e n ot i n t h ebusiness of condoning drugs or other interv entions tha treplace exercise itself . However, there are still manysitua tions, a s sta ted above, in wh ich the determinat ionof the biological mechanisms by which physical inactiv-ity leads to chronic diseases can be extremely benefi-cia l. For insta nce, medical r esea rchers may eventua llybe able t o ident ify hea lth-promotingbiochemica l pat h-w a y s t h a t a r e s h ut d ow n a s a r es ult of ph y sica li n a c t i v it y . Ap pl y i n g b i ol og i ca l l y m e ch a n i s t i c t e ch -niques for t he identifi cation of th e biochemical defectsoccu rrin g w ith p h ysical in a ctivi ty is cri t ical to t ar g et-in g th e se p ath w ays on a n in d ivid u al b asis for p h arm a -ceutical, gene thera py, or other intervention. Drugs a realready prescribed to decrease blood cholesterol levelsin in d ivid u als wh e n d ie t m o d ifi catio n fai ls . T h is is aform of p rim a ry p reven tion re qu irin g k n owle d g e o funderlying biological mechan isms (alth ough the preven-tion is st ill applied even a fter one or more risk factorsa re identifi ed). The public is current ly prescribed drugsth at targ e t b io ch e m ical p ath ways k e y to tre atin g d is-e ase s in a se con d ary an d te rt iary fash ion . I s p rescrib -ing pills in a proa ctive (i .e. , primar y preventive) man-n er t o i n di vi du a l s w h o a r e f or ce d t o b e p h y s ica l l yin active an y le ss im p o rtan t? I n su m m ary, fo r se ve ralreasons, it behooves public health to know the mode bywh ich t wo of th e stro n g est p red isposin g fa ctors forchronic disease (physical inactivity and inappropriatediet) act at a biologically mechanistic level.

    Rallying theTroops

    Why do we need a ma jor NIH initia tive devoted to theinvestigation of biological mechanisms leading to pri-

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    m a r y p r ev en t i on of ch r on i c d i s ea s e ? I n s h or t , i t i sbecause this obviously vital research area will remainu n d erd e ve lop ed u n less i t is h ig h lig h ted as an o th e rviab le we ap on in t h e w ar ag a in st ch ron ic d isease . Toch a n g e t h e cu r r en t s econ d a r y a n d t e r t ia r y f ocu s ofb iom ed i ca l r e se a r ch i s t o c h a n g e t h e w a y m os t ofsociety currently views health care options. However,su ch socie tal ch an g e d o es n ot occu r with o u t b ein g

    s pea r h e a d e d b y a n or g a n i zed e nt i t y t h a t p rom ot e sre se arch fu n d in g an d p u b lic e d u catio n in th e are a o fch an g e. C u rre n tly, t h e re are re lat ively few in vestig a-tors in the US accomplishing a small amount of promis-ing biologica lly mechanistic research int o primary pre-vention of chronic diseases. Because of its biologicallyd ive rse n atu re , th is re se arch is d istr ib u te d as a ve ryminor focus of several different funding sources (i .e. ,d i ffere n t in st i tu te s w ith in t h e N I H an d e lse wh e re).Therefore, most of this resea rch unfort una tely becomeslost in the shuffleas it is grouped with other researchp r oje ct s a n d p r op os a l s t h a t a p pe a r m or e i m pa c t f ulbecause t hey st udy seemingly more pressing second-ary an d te rt iary tre atm e n t issu e s. Estab l ish m e n t o f am ajo r re se arch in i t iat ive with in th e N I H to p ro m o tet h e s t u d y of b iol og ica l m ech a n i s m s u n d er l y in g t h eprimar y prevention of chronic disea se w ill enable thisdespera tely needed a rea of research to flourish.

    Biomedical research follows the funding money butr a r e l y v ice v er s a . U n f or t u n a t e ly, t h e r e i s cu r r en t l ylittle funding support for the biologically mechanisticstu d y of th e p rim ar y p reven tion of ch ron ic d iseasere g ard le ss o f th e in te rve n tio n al s trate g y. A t th e m o -m e n t, th e re are far to o fe w e xe rcise o r n u tri t io n re -s ea r ch er s t r a i n ed t o t a k e a d v a n t a g e of t h e pow e rdriving the modern scientific revolution of molecularbiology a nd genomics. Likewise, few molecular biolo-g ists ar e ap p rop riat e ly tra in ed to e xe cu te p rop erlydesigned exercise or nutrition experiments. What pro-grams exist to support the essential cross-training ofstudents and postdoctoral fellows between more basicresearch (such a s biochemistry a nd molecular biology)a nd more applied a reas of prima ry prevention (such a sexercise biology and nutrition)? No incentives are cur-rent ly in pla ce to encoura ge promising young investiga -to rs (o r e ve n e stab l ish e d in ve stig ato rs) to e n te r th isnewly emerging field. How can a fi eld thrive under suchcircu m sta n ces? Ch a n g e m u st occu r sim u lta n e ou slywith in th e b iom e d ical com m u n ity an d with in fu n d in ga gencies such a s the NIH if primary prevention is to bei n cl ud ed a s a f r es h r es ea r c h a p pr oa c h t ow a r d t h ebiological mechanisms of chronic disease; however, thef un d in g a g en ci es m u st m a k e t h e fi r s t m ov e i f t h echange is to occur at a ll .

    DRAWING UP NEW BATTLE PLANS

    F ield s of re sear ch stu d yin g th e b iolog ical m e ch a-nisms underlying primary prevention of chronic dis-eases ha ve been historica lly underfunded and unfortu-n at e ly n ow sta n d to r e ce ive e ven less su pp ort . Th eNIH s C enter for Scientific R eview is in t he process ofcompleting Phase 1 of a major overhaul of the systemb y w h i ch N I H r e sea r c h f u n d in g i s a w a r d e d . I n t h e ir

    initial 23-page draft of the Phase 1 proposal (43), theP a nel on S cientifi c Boundar ies for Review refers to then e ed t o su pp ort re sear ch fi e ld s t h at are n e wly e m e rg-ing, relevant to contemporary biomedical research, ofh ig h est im pact , an d tra n slat ion al (i .e ., a b le to tra n s-l a t e p rog r es s i n t h e b a s ic s ci en ce l a b or a t o ry i nt op rog re ss at th e b ed sid e). I n th e p rese n t p ap er, w eesta blish tha t fi elds investigat ing the biologica l mecha -

    n ism s u n d e rlyin g th e p rim ary p re ve n tio n o f ch ro n icdisease through interventions such as physical a ctivityand diet modification meet all of these criteria and farm ore . I n a d d it ion , w e e st im at e th a t p h ysical in activityim pacts 80 90% of th e 24 in te g rate d re vie w g rou p(I R G ) t o pi cs p r op os ed b y t h e C e n t er f or S c ie nt i fi cRe view (42, 43). Ho we ver, ou t of a lm o st 200 to talsu b to p ics l is te d with in th e I RG s o f th is Ph ase 1 p ro -posa l, we could not fi nd even one referra l in any form t oth e p rim ary p re ve n tio n o f ch ro n ic d ise ase o r to th einvestiga tion of physical a ctivity /ina ctivity a nd/or exer-cise (42, 43). Only brief mention was given to nutri-t ion . At m o st , th e se a re as wo u ld b e con sid ere d ascross-cutt ing issu es to be defi ned a s st udy sections inP h a s e 2 (t o b e o ut l in ed i n t h e n ex t 2 y r ) . Th i s i su n acce pta b le! I f th e p rim a ry p reve n tion of ch ron icd ise ase is o n ly se rve d b y th e ad d it io n o f an e ve n tu alstu dy section, it w ould be too litt le, too la te. The time t oact is now! The Center for Scientific Review has missedan e xcellen t op portu n ity to su p p ort a vision ary ap -p roach to fu tu re b iom e d ical r e sear ch th a t wo u ld p re-vent 0.25 million prema tur e dea th s/yr in t he US a s wella s t o p r e ve nt y ea r s of s u ff er i n g a n d t h e a s s oci a t e dfi na ncial burd en on America ns. An entit y devoted to th epromotion a nd funding of biologica lly m echa nistic r e-sear ch into the prima ry prevention of c


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